Back to EveryPatent.com
| United States Patent |
5,186,835
|
|
Masuoka
, et al.
|
February 16, 1993
|
Porous hydrophilic polypropylene membrane, method for production
thereof, and blood plasma separation apparatus
Abstract
A porous hydrophilic polypropylene membrane possessing a fine reticular
structure, which is characterized by the fact that at least either of the
opposite surfaces of membrane forms a surface layer of a reticular
structure substantially equal to that in the interior of membrane, the
membrane surfaces and the surfaces of pores in the membrane have a
hydrophilic polymer chemically bonded thereto, and the membrane is
composed substantially of a polypropylene possessing an average pore
diameter in the range 0.1 to 2.0 .mu.m, a bubble point of not more than
2.0 kg/cm.sup.2, a porosity in the range of 60 to 85%, and a water
permeability of not less than 2 ml/min.mmHgm.sup.2, a method for the
production thereof, and a blood plasma separation apparatus incorporating
such membranes in a housing are disclosed.
| Inventors:
|
Masuoka; Toshio (Tsukuba, JP);
Hirasa; Okihiko (Tsukuba, JP);
Onishi; Makoto (Fuji, JP);
Seita; Yukio (Fuji, JP)
|
| Assignee:
|
Agency of Industrial Science and Technology (Tokyo, JP);
Terumo Kabushiki Kaisha (Tokyo, JP)
|
| Appl. No.:
|
465240 |
| Filed:
|
April 26, 1990 |
| PCT Filed:
|
September 12, 1988
|
| PCT NO:
|
PCT/JP88/00920
|
| 371 Date:
|
April 26, 1990
|
| 102(e) Date:
|
April 26, 1990
|
| PCT PUB.NO.:
|
WO89/02303 |
| PCT PUB. Date:
|
March 23, 1989 |
Foreign Application Priority Data
| Sep 11, 1987[JP] | 62-226298 |
| Current U.S. Class: |
210/500.36; 210/500.38; 264/49 |
| Intern'l Class: |
B01D 067/00 |
| Field of Search: |
427/244,245,246
210/500.36,500.38,321.84,347,232,351
264/41,49
|
References Cited
U.S. Patent Documents
| 3083118 | Mar., 1963 | Bridgeford | 427/340.
|
| 4501793 | Feb., 1985 | Sarada | 210/500.
|
| 4597868 | Jul., 1986 | Watanabe | 210/347.
|
| 4845132 | Jul., 1989 | Masuoka et al. | 210/490.
|
| Foreign Patent Documents |
| 0249513 | Dec., 1987 | EP.
| |
| 0369014 | May., 1990 | EP.
| |
| 60-9460 | Mar., 1985 | JP.
| |
| 62-97603 | May., 1987 | JP.
| |
| 62-179540 | Aug., 1987 | JP.
| |
| 62-201604 | Sep., 1987 | JP.
| |
| 63-145662 | Jun., 1988 | JP.
| |
| 63-240902 | Oct., 1988 | JP.
| |
Primary Examiner: Spear; Frank
Attorney, Agent or Firm: Burns, Doane, Swecker & Mathis
Claims
We claim:
1. A porous hydrophilic polypropylene membrane possessing a fine reticular
structure, wherein at least either of the opposite surfaces of the
membrane forms a surface layer of a reticular structure substantially
equal to that in the interior of the membrane; the membrane surfaces and
the surfaces of pores in the membrane have a hydrophilic polymer
chemically bonded thereto, said hydrophilic polymer being at least one
member selected from the group of polymers consisting of the polymers
represented by the following formula I:
##STR24##
wherein R.sup.1 is H or CH.sub.3 and R.sup.2 is
##STR25##
wherein R.sup.3 and R.sup.4 are each an alkyl of 1 to 4 carbon atoms,
##STR26##
COOM, wherein m is a metallic atom, COOR.sup.5 NHR.sup.6, wherein R.sup.5
is an alkylene of 1 to 4 carbon atoms and R.sup.6 is an alkyl of 1 to 4
carbon atoms,
##STR27##
wherein R.sup.5 and R.sup.6 are as defined above and R.sup.7 is an alkyl
of 1 to 4 carbon atoms, or
##STR28##
providing that R.sup.1 is H where R.sup.2 is
##STR29##
and n is an integer in the range of 10 to 10.sup.4 ; the membrane is
composed substantially of a polypropylene possessing an average pore
diameter in the range of 0.1 to 2.0 .mu.m, a bubble point of not more than
2.0 kg/cm.sup.2, a porosity in the range of 60 to85%, and a water
permeability of not less than 2 ml/min.mmHg.m.sup.2 ; and the membrane is
prepared using liquid polyether as a cooling and solidifying liquid.
2. A porous hydrophilic polypropylene membrane according to claim 1,
wherein the ratio of shrinkage exhibited by the membrane after 20 minutes'
heat treatment at 120.degree. C. is not more than 5.0%.
3. A porous hydrophilic polypropylene membrane according to claim 1,
wherein the ratio of swelling exhibited by the membrane when it is wetted
is not more than 1.0%.
4. A porous hydrophilic polypropylene membrane according to claim 1,
wherein said hydrophilic polymer is represented by the following formula
II:
##STR30##
wherein n is as defined above, R.sup.8 is H or CH.sub.3 and R.sup.9 and
R.sup.10 each are an alkyl group, providing that the total number of
carbon atoms of R.sup.8, R.sup.9, and R.sup.10 is not more than 8.
5. A porous hydrophilic polypropylene membrane according to claim 1 wherein
the liquid polyether is polyethylene glycol.
6. A method for the production of porous hydrophilic polypropylene
membrane, which comprises mixing 100 parts by weight of a polypropylene
with 200 to 600 parts by weight of an organic filler uniformly dispersible
in the polypropylene in a molten state and 0.1 and 5.0 parts by weight of
a crystal seed-forming agent, discharging the resultant molten mixture
into a form flat sheet to form molten membrane, cooling and solidifying
the molten membrane with a liquid polyether, then extracting the organic
filler from the solidified molten membrane, thermally setting the flat
sheet, irradiating the resultant hydrophobic polypropylene membrane with a
low-temperature plasma thereby forming a polymerization-initiating point
on polypropylene molecules, reducing the pressure of the enveloping
atmosphere of the reaction system to below 0.01 torr, and subsequently
supplying a hydrophilic monomer to the reaction system thereby effecting
chemical linkage of a hydrophilic polymer to the surfaces of the membrane
and the surfaces of the pores in the membrane.
7. A method according to claim 6, wherein the contact of said molten
membrane with said cooling and solidifying liquid is accomplished by
disposing a guide roller in the cooling and solidifying liquid bath in
such a manner that part of said guide roller remains above the surface of
said cooling and solidifying liquid, and causing the molten membrane to be
discharged onto said guide roller and then guided into said cooling and
solidifying liquid by virtue of the rotation of said guide roller.
8. A method according to claim 6, wherein said polypropylene possesses a
melt index in the range of 5 to 70.
9. A method according to claim 8, wherein said crystal seed-forming agent
is incorporated in an amount in the range of 0.1 to 1.0 part by weight.
10. A method according to claim 6, wherein said polypropylene is a mixture
of 100 parts by weight of a polypropylene possessing a melt index in the
range of 5 to 40 with 0 to 150 parts by weight of a polypropylene
possessing a melt index in the range of 0.05 to 5.
11. A method according to claim 6, wherein said crystal seed-forming agent
is an organic heat-resistant substance possessing a melting point of not
lower than 150.degree. C. and a gelling point not lower than the
crystallization initiating temperature of said polypropylene.
12. A method according to claim 6, wherein said hydrophilic monomer is at
least one member selected from the group of compounds represented by the
following formula III:
##STR31##
wherein R.sup.1 is H or CH.sub.3 and R.sup.2 is
##STR32##
wherein R.sup.3 and R.sup.4 each stand for an alkyl of 1 to 4 carbon
atoms,
##STR33##
COOM, wherein M is a metallic atom, COOR.sup.5 NHR.sup.6, wherein R.sup.5
is an alkylene of 1 to 4 carbon atoms and R.sup.6 is an alkyl or 1 to 4
carbon atoms,
##STR34##
wherein R.sup.5 and R.sup.6 are as defined above and R.sup.7 is an alkyl
of 1 to 4 carbon atoms, or
##STR35##
providing that R.sup.1 is H where R.sup.2 is
##STR36##
and n is an integer in the range of 10 to 10.sup.4.
13. A method according to claim 12, wherein said hydrophilic monomer is
represented by the following formula IV:
##STR37##
wherein n is as defined above R.sup.8 is H or CH.sub.3 and R.sup.9 and
R.sup.10 each are an alkyl group, providing that the total number of
carbon atoms of R.sup.8, R.sup.9, and R.sup.10 is not more than 8.
14. A method according to claim 6 wherein the liquid polyether is
polyethylene glycol.
Description
DESCRIPTION
1. Technical Field
This invention relates to a porous hydrophilic polypropylene membrane, a
method for the production thereof, and a blood plasma separation
apparatus. More particularly, it relates to a flat sheetlike porous
polypropylene membrane, a method for the production thereof, and a blood
plasma separation apparatus. Still more particularly, this invention
relates to a flat sheetlike porous hydrophilic polypropylene membrane
which excels in compatibility to blood and dimensional stability and
which, when used for the separation of blood plasma, permits quick
separation of blood plasma and has a remote possibility of suffering from
embedment of blood cells or hemolysis, a method for the production
thereof, and a blood plasma separation apparatus.
2. Background Art
Heretofore, various permeable membranes have found utility for the
separation of blood into the component of blood cells and the component of
blood plasma. The permeable membranes are now used for the defecation of
blood plasma aimed at removal of abnormal protein, immune complex,
antigen, and antibody from patients with diseases due to abnormal immunity
such as general erythematodes, chronic arthrorheumatism, glomerular
nephtrities, and bulbospinal paralysis, for the preparation of blood
plasma agents for componental transfusion, for the pretreatment of
artificial kidneys, and so on. For example, cellulose acetate membranes
(Japanese Patent Laid-Open SHO 54(1979)-15,476), polyvinyl alcohol
membranes, polyester membranes, polycarbonate membranes, polymethyl
methacrylate membranes, polyethylene membranes (Japanese Patent Laid-Open
SHO 57(1982)-84,702), and polypropylene membranes have been used as
permeable membranes for the separation of blood plasma. These permeable
membranes are deficient in mechanical strength, porosity, and ability to
separate blood plasma. When they are used for the separation of blood
plasma, the red blood cells sustain injury due to clogging, the
complemental component in the blood plasma is suffered to undergo
activation, and the separated blood plasma is seriously injured
("Artificial Internal Organs," Vol. 16 No. 2, pp. 1045-1050) (1987).
A permeable membrane produced by mixing a polymer such as crystalline
polyolefin or polyamide which exhibits sparing solubility in solvents and
possesses expandability with a compound which possesses partial
compatibility with the polymer and exhibits ready solubility in solvents,
molding the resultant mixture into a film, a sheet, or a hollow article,
treating the molded article with a solvent, drying the wet molded article,
and thereafter stretching the dried molded article uniaxially or biaxially
by a ratio in the range of 50 to 15,000% has been proposed (Japanese
Patent Publication SHO 57(1982)-20,970). Since this membrane is stretched
for the purpose of enlarging the pores in diameter, it has a large thermal
shrinkage such that, when used as a medical material, it cannot tolerate
the impact of sterilization in an autoclave. Further, since this membrane
acquires its porous texture in consequence of the stretching, the pores
are linear extensions substantially parallel to the direction of all
thickness of the membrane and have a substantially uniform cross section
in the opposite surface parts and in the interior part thereof. When this
membrane is used for the separation of blood plasma, therefore, the pores
therein are highly liable to be clogged with proteins and blood cells.
Regarding the applicability of a permeable membrane to the separation of
blood plasma, polyolefin type macromolecular compounds have been
attracting attention as a material characterized by manifesting only an
insignificant complemental activity. Thus, permeable membranes using
polyolefin type macromolecular compounds are being studied with respect to
their feasibility in the intended application under discussion. For
example, a method for producing a porous membrane by melt mixing 10 to 80%
by weight of a paraffin with 90 to 20% by weight of a polypropylene resin,
extruding the resultant molten mixture through a die into a film, a sheet,
or a hollow fiber, leading the molded mixture still in the molten state
into a water bath kept at a temperature below 50.degree. C. to be suddenly
cooled and solidified, and subsequently extracting the paraffin from the
resultant solidified molded article has been disclosed (Japanese Patent
Laid-Open SHO 55(1980)-60,537). Since the porous membrane obtained by this
method undergoes the step of sudden cooling with cold water of large
specific heat, the pores in the surface parts and those in the inner part
of the membrane are both small in diameter and the membrane has a low
porosity. Thus, this membrane suffers from a low speed of permeation and
does not fit quick separation of blood plasma.
As means for cooling and solidifying the aforementioned molten mixture, a
method using a metallic roller and a method using a cooling and
solidifying liquid such as a paraffin which possesses high compatibility
with the aforementioned organic filler (Japanese Patent Application SHO
60(1985)-237,069) have been proposed. The porous membrane obtained by the
former method possesses extremely minute surface pore diameters and,
therefore, permits the permeation of blood plasma to proceed at a low
speed. In the latter method, the cooling and solidifying liquid has a
small specific heat as compared with water and, therefore, promotes
crystallization of polypropylene at a proper cooling speed. In the inner
part of the membrane, therefore, pores are formed in a large diameter
enough to permit separation of blood plasma. In the surface parts of the
membrane, however, there is formed a very large reticular structure which
is thought to have been formed because the polypropylene distributed in
the surface parts is caused to dissolve into the cooling and solidifying
liquid before it is solidified. The porous membrane possessing such
surface layers as described above suffers sparingly from clogging of pores
with proteins and permits the separation of blood plasma to proceed at a
satisfactorily high speed. It, however, has the possibility that, on
contact with the blood, the blood cells will be embedded will therein and
the blood cells so embedded undergo hemolysis under the impact of
pressure.
Hydrophobic membranes such as of polyolefins have no noticeably high
ability to activate the complemental system and nevertheless suffer from
the disadvantage that they are deficient in capacity for recovery of such
useful molecules as fibrinogen and a blood coagulating factor.
The hybrophobic membranes are further disadvantageous in respect that they
must be subjected to an extra treatment for impartation of hydrophilicity
prior to use.
A porous membrane which has the membrane surfaces and the surfaces of the
pores in the membrane rendered hydrophilic has been disclosed in Japanese
Patent Application SHO 61(1986)-103,011. In accordance with the method of
production as set forth in the specification (working examples and
photographs), the membrane to be produced tends to form in the surfaces
thereof pores of a large diameter such as to entail serious embodiment of
blood cells and consequent ready hemolysis. For the purpose of enabling
the membrane to manifest high compatibility to blood, mere incorporation
therein of a graft chain of a hydrophilic monomer is not sufficient. The
membrane in its simple form is required to have a water-soluble
macromolecular compound chemically bonded thereto.
An object of this invention, therefore, is to provide a novel porous
hydrophilic polypropylene membrane and a method for the production
thereof.
Another object of this invention is to provide a flat sheetlike porous
hydrophilic polypropylene membrane to be used for the isolation of blood
plasma by separation of blood into the portion of blood cells and the
portion of blood plasma and the removal of microorganisms from blood, for
example.
Yet another object of this invention is to provide a flat sheetlike porous
hydrophilic polypropylene membrane which excels in compatibility to blood
and dimensional stability and which, when used for the isolation of blood
plasma from blood, permits quick separation of blood plasma, sparingly
inflicts injury to the isolated blood plasma, and has little possibility
of entailing embodiment of blood cells and hemolysis and a method for the
production thereof.
DISCLOSURE OF INVENTION
The objects described above are accomplished by a porous hydrophilic
polypropylene membrane possessing a fine reticular structure, which is
characterized by the fact that at least either of the opposite surfaces of
membrane forms a surface layer of a reticular structure substantially
equal to that in the interior of membrane, the membrane surfaces and the
surfaces of pores in the membrane have a hydrophilic polymer chemically
bonded thereto, and the membrane is composed substantially of a
polypropylene possessing an average pore diameter in the range of 0.1 to
2.0 .mu.m, a bubble point of not more than 2.0 kg/cm.sup.2, a porosity in
the range of 60 to 85%, and a water permeability of not less than 2
ml/min.mmHg.m.sup.2.
This invention further discloses a porous hydrophilic polypropylene
membrane whose ratio of shrinkage after a heat treatment at 120.degree. C.
for 20 minutes is not more than 5.0%.
This invention further discloses a porous hydrophilic polypropylene
membrane whose ratio of swelling on being wetted is within 1.0%. This
invention further discloses a porous hydrophilic polypropylene membrane
whose hydrophilic polymer is at least one member selected from the group
of polymers represented by the following formula I:
##STR1##
wherein R.sup.1 is H or CH.sub.3 and R.sup.2 is
##STR2##
wherein R.sup.3 and R.sup.4 are each an alkyl of 1 to 4 carbon atoms,
##STR3##
COOM, wherein M is a metallic element, COOR.sup.5 NHR.sup.6, wherein
R.sup.5 is an alkylene of 1 to 4 carbon atoms and R.sup.6 is an alkyl of 1
to 4 carbon atoms,
##STR4##
wherein R.sup.5 and R.sup.6 are as defined above and R.sup.7 is an alkyl
of 1 to 4 carbon atoms, or
##STR5##
providing that R.sup.1 is H where R.sup.2 is
##STR6##
and n is an integer in the range of 10 to 10.sup.4. Further this invention
discloses a porous hydrophilic polypropylene membrane whose hydrophilic
polymer is represented by following formula II:
##STR7##
wherein n is as defined above, R.sup.8 is H or CH.sub.3 and R.sup.9 and
R.sup.10 each are an alkyl group, providing that the total number of
carbon atoms of R.sup.8, R.sup.9, and R.sup.10 is not more than 8.
The objects described above are further accomplished by a method for the
production of porous hydrophilic polypropylene membrane, which comprises
mixing 100 parts by weight of a polypropylene with 200 to 600 parts by
weight of an organic filler uniformly dispersible in the polypropylene in
a molten state and 0.1 to 5.0 parts by weight of a crystal seed-forming
agent, discharging the resultant molten mixture into a flat sheet to form
a molten membrane, cooling and solidifying the molten membrane with a
liquid polyether, then extracting the organic filler from the solidified
molten membrane, thermally setting the molten membrane, irradiating the
resultant hydrophobic polypropylene membrane with a low-temperature plasma
thereby forming a polymerization-initiating point on polypropylene
molecules, reducing the pressure of the enveloping atmosphere of the
reaction system to below 0.01 torr, and subsequently supplying a
hydrophilic monomer to the reaction system thereby effecting chemical
linkage of a hydrophilic polymer to the surfaces of the membrane and the
surfaces of the pores in the membrane.
This invention further discloses a method for the production of a porous
hydrophilic polypropylene membrane, wherein the contact of the molten
membrane with the cooling and solidifying liquid is accomplished by
disposing a guide roller in the cooling and solidifying liquid bath in
such a manner that part of the guide roller remains above the surface of
the cooling and solidifying liquid, and causing the molten membrane to be
discharged onto the guide roller and then guided into the cooling and
solidifying liquid by virtue of the rotation of the guide roller.
This invention further discloses a method wherein the polypropylene
possesses a melt index in the range of 5 to 70. Further, this invention
discloses a method wherein the polypropylene is a mixture of 100 parts by
weight of a polypropylene possessing a melt index in the range of 5 to 40
with 0 to 150 parts by weight of a polypropylene possessing a melt index
in the range of 0.05 to 5. This invention further discloses a method
wherein the blood plasma seed-forming agent is incorporated in an amount
in the range of 0.1 to 1.0 part by weight. This invention further
discloses a method wherein the crystal seed-forming agent is an organic
heat-resistant substance possessing a melting point of not lower than
150.degree. C. and a gelling point not lower than the crystallization
starting point of the polypropylene. Further, this invention discloses a
method wherein the hydrophilic polymer is at least one member selected
from the group of compounds represented by the following formula III:
##STR8##
wherein R.sup.1 is H or CH.sub.3 and R.sup.2 is
##STR9##
wherein R.sup.3 and R.sup.4 each are an alkyl of 1 to 4 carbon atoms,
##STR10##
COOM, wherein M is a metallic element, COOR.sup.5 NHR.sup.6, wherein
R.sup.5 is an alkylene of 1 to 4 carbon atoms and R.sup.6 is an alkyl of 1
to 4 carbon atoms,
##STR11##
wherein R.sup.5 and R.sup.6 are as defined above and R.sup.7 is an alkyl
of 1 to 4 carbon atoms, or
##STR12##
providing that R.sup.1 is H where R.sup.2 is
##STR13##
and n is an integer in the range of 10 to 10.sup.4. Further this invention
discloses a method wherein the hydrophilic monomer is represented by the
following formula (IV):
##STR14##
wherein R.sup.8 is H or CH.sub.3 and R.sup.9 and R.sup.10 each are an
alkyl group, providing that the total number of carbon atoms of R.sup.8,
R.sup.9, and R.sup.10 is not more than 8.
The objects described above are accomplished by a blood plasma separation
apparatus comprising a plurality of separation membrane units each formed
by vertically opposing face to face two porous hydrophilic polypropylene
membranes each possessing a fine reticular structure and at least either
of the opposite surfaces of membrane forming a surface layer of a
reticular structure substantially equal to that in the interior of
membrane, the membrane surfaces and the surfaces of pores in the membrane
having a hydrophilic polymer chemically bonded thereto, and the membrane
being composed substantially of a polypropylene possessing an average pore
diameter in the range of 0.1 to 2.0 .mu.m, a bubble point of not more than
2.0 kg/cm.sup.2, a porosity in the range of 60 to 85%, and a water
permeability of not less than 2 ml/min. mmHg.m.sup.2 thereby interposing a
blood plasma flow path between the two opposed membranes, sealing the
peripheral part of the flow path, and providing at least one of the
separation membranes with a blood plasma outlet, a case accommodating the
plurality of separation membrane units in a superposed state and provided
with a blood inlet, a blood outlet, and a blood plasma outlet, and means
for establishing communication between the blood plasma outlet of each of
the separation membrane units and the blood plasma outlet of the case.
This invention further discloses a blood plasma separation apparatus
wherein the porous hydrophilic polypropylene membrane exhibits a ratio of
shrinkage of not more than 5.0% after a heat treatment at 120.degree. C.
for 20 minutes. This invention further discloses a blood plasma separation
apparatus wherein the porous hydrophilic polypropylene membrane exhibits a
ratio of swelling within 1.0% on being wetted.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is an electron micrograph illustrating the surface structure of a
porous hydrophilic polypropylene membrane according to the present
invention obtained in Example 1.
FIG. 2 is an electron micrograph illustrating the cross section of the same
porous membrane.
FIG. 3 is an apparatus of production illustrating a method of production of
this invention.
FIG. 4 is a cross section illustrating a blood plasma separation apparatus
according to the present invention.
FIG. 5 is a schematic view of circuit of a test on blood plasma separation.
FIG. 6 is an electron micrograph illustrating the surface of the porous
hydrophilic membrane of Example 1 after use of the membrane in the
separation of bovine blood plasma.
FIG. 7 is an electron micrograph illustrating the surface of the porous
hydrophilic membrane of Control 1 after use of the membrane in the
separation of bovine blood plasma.
BEST MODE FOR CARRYING OUT THE INVENTION
The porous hydrophilic polypropylene membrane of this invention is a
membrane having a wall thickness in the range of 30 to 300 .mu.m,
preferably 60 to 200 .mu.m, and having a hydrophilic polymer chemically
bonded to the surfaces of membrane and the surfaces of porous in the
membrane. The structure of the porous hydrophilic polypropylene membrane
is variable with the conditions of the formation of the membrane. When a
polyethylene glycol (molecular weight: 200) is used as a cooling and
solidifying liquid as described, the produced membrane possesses such a
structure as shown in the scanning electron micrographs of FIG. 1 and FIG.
2. To be specific, a fine reticular structure composed of intertwined
threads each formed of a chain of polypropylene particles is developed
three-dimensionally. Since the surface parts of membrane possess a
reticular structure substantially similar to that in the inner part of
membrane, the membrane used for separation of blood plasma has a very
remote possibility of entailing embedment of blood cells or hemolysis.
Since this membrane has the reticular structure developed isotropically
unlike the porous membrane produced by the stretching method, it sustains
the minimal thermal shrinkage during the treatment in an autoclave. Thus,
it tolerates various methods of sterilization.
In order for the porous hydrophilic polypropylene membrane of this
invention to manifest amply the ability to separate blood plasma, it is
desired to possess an average pore diameter in the range of 0.1 to 2.0
.mu.m, preferably 0.2 to 1.0 .mu.m, a bubble point of not more than 2.0
kg/cm.sup.2, preferably in the range of 0.2 to 1.6 kg/cm.sup.2, a porosity
in the range of 60 to 85%, preferably 65 to 80%, and a water permeability
exceeding 2 ml/min.mmHg.m.sup.2, preferably falling in the range of 4 to
400 ml/min.mmHg.m.sup.2. If the average pore diameter is less than 0.1
.mu.m, decreasing in permeability of high molecular weight proteins etc.
(e.g. blood coagulating factor VIII or various immune complexes) in blood
plasma makes separation and fraction difficult. Conversely, if this
average pore diameter exceeds 2.0 .mu.m, the membrane during the course of
separation of blood plasma suffers blood cells to be embedded therein or
to be decayed readily by hemolysis and the polypropylene membrane is
degraded in physical properties and is embrittled possibly to the extent
of insufficiently fulfiling the function in the intended use. If the
bubble point exceeds 2.0 kg/cm.sup.2, the membrane has no sufficient
capacity for separation of blood plasma. If the porosity is less than 60%,
the membrane possesses an insufficient capacity for separation of blood
plasma. Conversely, if the porosity exceeds 85%, the polypropylene
membrane is degraded in physical properties and is embrittled possibly so
much as to manifest a poor performance in the intended use. If the water
permeability is less than 2 ml/min.mmHg.m.sup.2, the membrane is deficient
in the ability to effect separation of blood plasma.
The terms and the method of determination used in the present intention are
as follows.
The "average pore diameter" refers to the magnitude maximum value of d V/d
log r (wherein V is a pore volume and r is a pore radius) which was
determined with a mercury porosimeter. The bubble point refers to the
magnitude which was determined by the modified method of ASTM F 316, using
a stainless steel holder 47 mm in diameter and a liquid phase of isopropyl
alcohol, increasing the pressure exerted upon the sample membrane, and
finding the particular magnitude of pressure at which a series of bubbles
of nitrogen began to rise incessantly up the isopropyl alcohol from the
central part of the filter.
The wall thickness of membrane refers to the magnitude which was determined
with a micrometer.
The water permeability refers to the magnitude which was actually
determined with distilled water at 25.degree. C. under the pressure of 0.7
kgf/cm.sup.2.
The porosity (P) refers to the magnitude which was determined by immersing
a sample porous membrane in ethanol, displacing the ethanol in the
membrane with water thereby hydrating the membrane, taking the weight (Ww)
of the hydrated membrane, and calculating the following formula, where Wd
is the weight of the membrane in a dry state and a (g/cm.sup.3) is the
density of polymer.
##EQU1##
The swelling ratio refers to the magnitude which was actually determined by
immersing a sample membrane in distilled water at 25.degree. C. for five
minutes and measuring changes in size of the membrane before and after the
immersion.
The hydrophilic polymer to be chemically bonded to the hydrophobic
polypropylene through graft polymerization has no restriction except for
the sole requirement that it should be hydrophilic. It is, however,
desired not to contain any --OH group because the activation of the
complemental system can be curbed more in the absence of this group than
in the presence thereof. The monomer unit which is capable of forming the
hydrophilic polymer is at least one compound represented by the following
formula I':
##STR15##
wherein R.sup.1 is H or CH.sub.3 and R.sup.2 is
##STR16##
wherein R.sup.3 and R.sup.4 each stand for an alkyl of 1 to 4 carbon
atoms,
##STR17##
COOM, wherein M is a metallic atom, COOR.sup.5 NHR.sup.6, wherein R.sup.5
is an alkylene of 1 to 4 carbon atoms and R.sup.6 is an alkyl of 1 to 4
carbon atoms,
##STR18##
wherein R.sup.5 and R.sup.6 are as defined above and R.sup.7 is an alkyl
of 1 to 4 carbon atoms, or
##STR19##
providing that R.sup.1 is H where R.sup.2 is
##STR20##
As typical examples of the hydrophilic polymer, there may be mentioned
poly-N-vinyl pyrrolidone, poly(meth)acrylamides, poly-N-lower alkyl
(meth)acrylamides, poly(meth)acryloyl morpholines, and diacetone
(meth)acrylamides. Optionally, the hydrophilic polymer may be a copolymer
of such monomer units as mentioned above. The degree of polymerization of
the hydrophilic polymer is in the range of 10 to 10.sup.4, preferably
10.sup.2 to 10.sup.3.
The hydrophilic polymer is desired to be in alkyl (meth)acrylamide
represented by the following formula II:
##STR21##
wherein n is as defined above, R.sup.8 is K or CH.sub.3 and R.sup.9 and
R.sup.10 each are an alkyl group, providing that the total number of
carbon atoms, of R.sup.8, R.sup.9 and R.sup.10 is not more than 8.
The hydrophilic polymer which is formed of an alkyl acrylamide of the
formula II possesses a strongly hydrophobic part in the molecular unit
thereof in site of its very large affinity for water. It, therefor,
exhibits highly satisfactory affinity for polypropylene and allows the
binding reaction within the pores to proceed smoothly and remains in a
stable state on the surfaces of membrane. Further, since this membrane
does not contain in the molecular unit thereof what activate the
complemental system (such as, for example, a hydroxyl group), it possesses
high compatibility to blood.
The hydrophilic monomer to be bonded by a reaction to the porous
hydrophobic polypropylene membrane is desired to be a monomer represented
by the following formula III:
##STR22##
wherein R.sup.1 and R.sup.2 are as defined above, preferably an alkyl
(meth)acrylamide represented by the following formula IV:
##STR23##
wherein R.sup.8, R.sup.9 and R.sup.10 are as defined above.
The water-soluble polymer bonded to the surfaces of membrane and to the
surfaces of pores in the membrane fulfils the role of curbing the
adsorption of such blood plasma proteins as fibrinogen and blood
coagulating factor to the membrane, alleviating the clogging of membrane,
and enhancing the compatibility of membrane to blood.
The porous hydrophilic polypropylene membrane having these characteristic
properties is produced as follows. First, the porous hydrophobic
polypropylene membrane is obtained, as described in the specification of
U.S. Pat. No. 4,743,375, for example, by supplying a blend 11 comprising
polypropylene, an organic filler uniformly dispersible in the
polypropylene in a molten state and readily soluble in an extractant to be
used, and optionally a crystal seed-forming agent, as illustrated in FIG.
3, through a hopper 12 to kneader such as, for example, a twin-screw type
extruder 13, thereby producing a molten mixture, discharging the molten
mixture through a die 14, bringing the discharged mixture into contact
with a guide roller 16 disposed inside a cooling tank 15 filled with a
cooling and solidifying liquid 17 above the surface of the cooling and
solidifying liquid 17, allowing the mixture to be led into the cooling and
solidifying liquid 17 by virtue of the rotation of the guide roller 16,
and removing the organic filler from the resultant membrane by contact
thereof with an extractant incapable of dissolving the hydrophobic
polymer. Otherwise, the membrane may be produced by subjecting the melted
mixture to the casting method by the use of suitable coagulating solvent.
In the procedure described above, the contact between the molten membrane
and the cooling and solidifying liquid is depicted as attained by virtue
of a guide. This contact may be otherwise attained by directly discharging
the molten membrane into the cooling and solidifying liquid. The molten
membrane is completely cooled and solidified while it is being passed
through the cooling tank 15. Then, the solidified membrane is taken up on
a winding roller 18. In the meantime, the cooling and solidifying liquid
which is supplied through a line 19 is then discharged in a line 20,
cooled to a prescribed temperature by a cooling device (such as, for
example, a heat exchanger) 20a, and recycled. The membrane taken up in a
roll is then led into an extraction tank (not shown) filled with an
extractant to effect extraction of the organic filler from the membrane.
The membrane departing from the extraction tank may be optionally
subjected to the steps of re-extraction, drying heat treatment, etc. For
the sake of stabilization of the structure and permeation property of the
porous membrane to be produced, the heat treatment is desired to be
performed on the membrane while the membrane is kept immobilized in a
fixed length. The extraction of the organic filler may be effected with
the extraction tank which is disposed at a stage preceding that of
winding.
By placing the porous hydrophobic polypropylene membrane thus produced in a
reactor, irradiating it with a low-temperature plasma so as to form
polymerization-initiating points on the molecules of polypropylene,
reducing the pressure of the enveloping atmosphere to a level below 0.01
torr, and supplying a hydrophilic monomer to the reaction system,
water-soluble polymer chains are allowed to grow as bonded to the surface
of membrane and the surfaces of pores in the membrane. Then, water-soluble
linear polymer chains are quickly synthesized on the surfaces of membrane
and on those of pores in the membrane as well by irradiating the membrane
with a low-temperature plasma and thoroughly removing the product of
decomposition with the plasma and the gas.
The polypropylene to be used as the raw material in the production by the
method of this invention is not limited to propylene homopolymer. A block
polymer of polypropylene as a main component with other monomer (such as,
for example, polyethylene) may be used. The polypropylene to be used is
desired to possess a melt index (M.I.) in the range of 5 to 70, preferably
5 to 40. For the purpose of increasing the strength of membrane, the raw
material is desired to incorporate therein a polypropylene of a large
molecular weight, i.e. a low level of M.I. For example, a raw material
obtained by kneading 100 parts by weight of polypropylene possessing an
M.I. range of 1.5 to 40 with 20 to 100 parts by weight of polypropylene
possessing an M.I. range of 0.05 to 5 is used advantageously. In all the
species of polypropylene usable as the raw material, propylene homopolymer
particularly of the grade possessing high crystallinity is used most
desirably. The organic filler is required to be uniformly dispersible in
the aforementioned polypropylene in the molten state and to be readily
soluble in the extractant as described hereinafter. As examples of the
organic filler, various hydrocarbons such as liquid paraffins (number
average molecular weight 100 to 2,000), .alpha.-olefin oligomers
[represented by ethylene oligomers (number average molecular weight 100 to
2,000), propylene oligomers (number average molecular weight 100 to
2,000)], and ethylene-propylene oligomers (number average molecular weight
100 to 2,000)], and paraffin waxes (number average molecular weight 100 to
2,500)], can be mentioned. Among other organic fillers enumerated above,
liquid paraffins prove to be particularly desirable.
The mixing ratio of the organic filler to the propylene is 200 to 600 parts
by weight, preferably 300 to 500 parts by weight, of the organic filler to
100 parts by weight of the polypropylene. If the amount of the organic
filler is less than 200 parts by weight, the produced porous polypropylene
membrane is deficient in porosity and water permeability and offers no
sufficient permeation. If this amount exceeds 600 parts by weight, the
mixture is excessively deficient in viscosity and the membrane suffers
from poor moldability. The blend of raw materials is prepared by melting
and mixing the component raw materials in a prescribed composition with an
extruder such as, for example, a twin-screw type extruder, extruding the
resultant molten mixture, and then pelletizing the extruded mixture.
The crystal seed-forming agent to be incorporated in the raw materials for
use in the present invention is an organic heat-resistant substance
possessing a melting point exceeding 150.degree. C., preferably falling in
the range of 200.degree. to 250.degree. C., and a gelling point exceeding
the crystallization-initiating temperature of the polypropylene to be
used.
The incorporation of the crystal seed-forming agent is aimed at permitting
ample reduction in particle diameter of the polypropylene and necessary
control of the gaps in the solid phase, namely the diameter of the pores
formed in the membrane. As examples of the crystal seed-forming agent,
1.3, 2.4-di(alkylbenzylidene) sorbitols such as 1.3, 2.4-di-benzylidene
sorbitol, 1.3 2.4-di-p-methylbenzylidene sorbitol and 1.3,
2.4-di-p-ethylbenzylidene sorbitol bis(4-t-butylphenyl)sodium phosphate,
and sodium benzoate may be mentioned. Among other crystal seed-forming
agents enumerated above, 1.3, 2.4-di-benzylidene sorbitol, 1.3,
1.4-di-p-methylbenzylidene sorbitol and 1.3, 2.4-di-p-ethylbenzylidene
sorbitol prove to be particularly desirable in respect that they dissolve
sparingly into blood.
The mixing ratio of the crystal seed-forming agent to the polypropylene is
0.1 to 5 parts by weight, preferably 0.2 to 1.0 part of weight, of the
crystal seed-forming agent to 100 parts by weight of the polypropylene.
The porous hydrophilic polypropylene membrane obtained as described above,
on 20 minutes' heat treatment at 120.degree. C., exhibits a ratio of
shrinkage not exceeding 5.0%, preferably not exceeding 0.5%. On being
wetted it exhibits a swelling ratio not exceeding 1.0%, preferably not
exceeding 0.5%. The wall thickness of this hydrophilic membrane requires
to be such extent as not to clog the minute pores from viewpoint of
ability to separate the blood plasma. It is, for example, not exceeding
200 nm, preferably not exceeding 100 nm.
The porous hydrophilic polypropylene membrane is obtained as described
above. The uses to be found for this membrane include a blood plasma
separation membrane for the separation of blood into a component of blood
cells and blood plasma and a microfilter for the removal of microorganisms
from blood, for example. It is used particularly advantageously as a blood
plasma separation membrane in applications such as donor plasmapheresis
which effective use of blood plasma to be separated or for therapy of
immunodisease.
The membrane which is obtained as described above is employed for a varying
use, depending on the particular attributes of the membrane body 1 in
terms of permeation. It manifests an outstanding performance particularly
when it is incorporated as a blood plasma separation membrane in a module
as shown below.
FIG. 4 illustrates in cross section a typical blood plasma separation
apparatus as one embodiment of this invention. In this embodiment, within
a case which comprises a cylindrical case body 24 provided in the central
part of the upper plate thereof with a blood inlet 21, in the peripheral
part of an upper plate thereof with blood plasma outlets 22, and on the
lateral wall thereof with a blood outlet 23 and a bottom lid member 26
fitted on the circumferentially edge thereof with an O ring, a plurality
of membrane units 31 each comprising a circular blood plasma flow
path-forming member 27 made of screen mesh or non-woven fabric, provided
at the center thereof with an opening part 28 and in the peripheral part
thereof with blood plasma passage holes 29, and adapted to have the outer
edge thereof nipped between blood plasma separation membranes 10a, 10b,
and two seals one for the outer edge thereof and the other for the central
opening part are superposed in such a manner as to sandwich flow path
regulating members 32 adapted to apply a sealing material 30 around the
periphery of the blood plasma passage holes 29 and provided with a
plurality of minutes protuberances 34. The membrane units 31 and the flow
path regulating members 32 are integrally joined through the medium of the
sealing members 30.
In the flow path regulating members 32, the minute protuberances 34 are
desired to possess a height in the range of 20 to 200 microns and diameter
at the base in the range of 100 to 1,000 microns, the apexes of these
minute protuberances are to be separated by a fixed interval in the range
of 300 to 2,000 microns, and the minute protuberances are to occupy a
total area in the range of 3 to 20% of the entire surface area of the
membrane. Preferably, the minute protuberances possess a height in the
range of 50 to 100 microns and a diameter at the base in the range of 200
to 500 microns, the apexes of the minute protuberances are separated by a
fixed interval in the range of 500 to 1,000 microns, and the minute
protuberances occupy a total area in the range of 5 to 15% of the total
surface area of the membrane.
To be specific, the height of the individual minute protuberances on the
surface of the permeation membrane constitute an important factor for
regulating the thickness of the flow path for the body fluid. From the
engineering point of view, if the height of these minute protuberances is
less than 20 microns, the flow path for body fluid has a thickness so
small as to induce heavy pressure loss. If the height exceeds 200 microns,
the shear speed cannot be increased enough to obtain ample permeation of
the body fluid.
All these matters considered, the height of these minute protuberances is
desired to fall in the range of 20 to 200 microns. Though this height is
desired to be uniform, the uniformity is not necessarily critical.
Optionally, this height may be gradually changed in the direction of the
flow of the body fluid.
Now, this invention will be described more specifically below with
reference to working examples.
EXAMPLE 1 AND CONTROL 1
With a twin-screw type extruder (produced by Ikegal Iron Works, Ltd. and
marketed under product code of "PCM-30-25"), 100 parts by weight of a
mixture of two species of polypropylene having melt indexes of 30 and 0.3
(mixing ratio 100:30 by weight), 400 parts by weight of liquid paraffin
(number average molecular weight 324), and 0.3 part by weight of
1,3,2,4-bis(p-ethylbenzylidene)sorbitol as a crystal seed-forming agent
were melted, kneaded, and pelletized. In the same extruder, the pellets
were melted at a temperature in the range of 150.degree. to 200.degree.
C., extruded, through a T die 0.6 mm in slit width into the ambient air,
allowed to fall onto a guide roller of a cooling liquid tank installed
directly below the T die, allowed to be led into the cooling and
solidifying liquid in the tank by virtue of rotation of the roller to be
cooled and solidified therein, and then taken up in a roll. The cooling
and solidifying liquid and the temperature thereof were varied as
indicated in Table 1. The rolled film was cut into fixed lengths (about
200.times.200 mm). A cut piece of film, fixed in both the longitudinal and
lateral directions, was immersed a total of four times each for 10 minutes
in 1,1,2-trichloro-1,2,2-trifluoroethane (kept at 25.degree. C.) to
extract the liquid paraffin and then subjected to two minutes' heat
treatment in the air at 135.degree. C.
The porous hydrophobic polypropylene membrane thus obtained was irradiated
with a low-temperature plasma (argon 0.1 torr) for 10 seconds and, with
the pressure of the enveloping air lowered to 0.001 torr, N,N-dimethyl
acrylamide was supplied and caused to react upon the membrane at
25.degree. C. for five minutes. The membrane undergone this treatment was
washed with methanol for two days and then dried, to obtain a porous
hydrophilic polypropylene membrane having poly(N,N-dimethyl acrylamide), a
hydrophilic polymer, bonded to the surfaces thereof and the surface of
pores formed therein.
FIG. 1 and FIG. 2 are electron micrographs illustrating structures of the
porous hydrophilic polypropylene membrane obtained in Example 1; FIG. 1
depicting a surface of the membrane and FIG. 2 a cross section thereof.
The porous hydrophilic membranes of Example 1 and Control 1 were each
incorporated in a blood separation module 40 and stowed in a flask 41
provided with a stirrer 42 and used for the separation of blood plasma
from bovine blood. FIG. 6 and FIG. 7 are electron micrographs illustrating
the surfaces of the membranes resulting from the blood plasma separation.
In the diagram of FIG. 5, P stands for a pump and G1 to G3 stand each for
a pressure gauge. In the membrane of Example 1, virtually no sign of
embedment of blood cells in the membrane surface was observed unlike the
membrane of Control 1. The results of the test are shown in Table 1.
EXAMPLE 2 AND CONTROLS 2 AND 3
A hydrophobic polypropylene membrane possessing the same membrane structure
as that of Example 1 and having no water-soluble polymer bonded to the
surfaces of membrane or to the surfaces of pores in the membrane was used
in Control 2 and a cellulose acetate membrane (produced by Toyo Roshi
Company), a porous hydrophilic membrane possessing a pore diameter roughly
equal to that of the membrane of Example 2 was used in Control 3.
These porous blood plasma separation membranes were subjected to an in
vitro test for blood plasma separation using human blood. As an index of
the recovery of a coagulating factor in the filtered blood plasma, the
ratios of recovery of fibrinogens F, VIII: C were determined. As an index
of the activation of the complemental system, the C.sub.3a a concentration
in the filtered blood plasma was determined.
a disk-shaped module of membrane 130 cm.sup.2 in surface area was tested
with a circuit illustrated in FIG. 3 under the conditions of 25 mmHg of
filtration pressure and 37.degree. C. of temperature. The data obtained in
the initial stage of filtration (10 minutes following the start of
separation), in which the structures of the surfaces of membrane and the
surfaces of pores in the membrane had conspicuous influences upon the
adsorption of blood plasma proteins and the activation are shown in Table
2. The porous hydrophilic polypropylene membrane of the present invention
recovered the fibrinogens F. VIII:C in high ratios and caused activation
of the complemental system only sparingly, indicating excellence in the
blood binding property.
The results are shown in Table 2.
TABLE 1
__________________________________________________________________________
Water perme-
Cooling and Cooling Wall ability
Average
Bubble
Thermal
Swelling
Embedment
solidifying tempera-
Porosity
thickness
(ml/min. -
Pore point
shrinkage
ratio
of blood
liquid ture (.degree.C.)
(%) (.mu.m)
mmHg.m.sup.2)
diameter(.mu.m)
(kg/cm.sup.2)
(%) (%) cells
__________________________________________________________________________
Example
Polyethylene
35 65 146 39 0.42 1.1 1.4 0.3 None
1 glycol (FIG. 6)
Control
Liquid 38 65 120 48 0.39 1.1 1.3 0.3 Observed
1 paraffin (FIG.
__________________________________________________________________________
7)
TABLE 2
______________________________________
Example
Control Control
2 2 3
______________________________________
Wall thickness (.mu.m)
140 140 150
Bubble point (kg/cm.sup.2)
1.2 1.2 1.1
C.sub.3a in filtered blood
1.9 5.6 21.2
plasma/c.sub.3a in blood
plasma before filtration
Ratio of recovery of
93 54 91
fibrinogen (%)
Ratio of recovery of
90 73 92
fibrinogens F.VIII: C (%)
Ratio of recovery of
92 91 89.0
total proteins (%)
______________________________________
INDUSTRIAL APPLICABILITY
The porous hydrophilic polypropylene membrane of this invention, as
described above, is a porous hydrophilic membrane possessing a fine
reticular structure. This porous membrane has formed in at least either of
the opposite surface parts thereof a surface layer of a reticular
structure roughly equal to that in the inner part of membrane and has a
water-soluble polymer chemically bonded to the surfaces of membrane and
the surfaces of pores in the membrane. When this membrane is used as a
blood plasma separation membrane, therefore, it has only a remote
possibility of suffering blood cells to be embedded in the membrane or to
be decayed by hemolysis. Further, since the water-soluble polymer bonded
to the surfaces of pores in the member are in a state of generating rapid
movement as though it were partially dissolved in blood plasma, it curbs
the degeneration of blood plasma proteins by adsorption and represses the
injury of separated blood plasma. As the result, the membrane recovers the
coagulating factor in blood plasma in a high ratio and entails the
activation of the complemental system only sparingly, indicating high
compatibility of the membrane to blood. Thus, the membrane manifests an
outstanding effect as a blood plasma separation membrane in the therapy of
deceases due to immune abnormality and in the collection of blood plasma
for componental transfusion. Owing to its excellent compatibility to
blood, the porous hydrophilic polypropylene membrane not only serves
advantageously as a membrane for the treatment of blood and as a porous
carrier but also manifests a notable effect as an ultrafiltration
separation membrane for attaining removal of microbes without entailing
the problem of clogging in the field of pharmaceutical industry and
foodstuff industry.
Since the porous hydrophilic polypropylene membrane of this invention is
capable of retaining an excellent dimensional stability even during the
course of heat treatment or swelling treatment, it can be used in the
activities of pharmaceutical industry and foodstuff industry which require
sterilizing operations. Further, it can preclude the channeling phenomenon
due to the deformation by swelling which often poses a problem when the
membrane is used in the form of a module.
The method of production contemplated by this invention permits the porous
membrane possessing such outstanding properties as described above to be
produced easily.
Top